Compositions and method for treating gastroduodenal ulcer and gastric hypersecretion with a 2-pyridyl thioacetamide or a salt thereof

ABSTRACT

Pharmaceutical compositions containing 2-pyridyl thioacetamide and its salts and method of treating gastroduodenal ulcer and gastric hypersecretion by the same.

Elite Stat Malen et al.

[451 Aug. 1,1972

[54] COWOSTTIONS AND METHOD FOR TREATING GASTRODUODENAL ULCER AND GASTRIC HYPERSECRETION WITH A 2- PYRIDYL THIOACETAMIDE OR A SALT THEREOF [72] Inventors: Charles Malen, Fresnes; Xavier Pascaud, Paris, both of France [73] Assignee: Societe en nom Collectif Science Union et Cie, Societe liancaise De Recherche Medicale, Suresnes, France:

[22] Filed: March 31, 1971 [21] Appl. No.: 130,001

Related US. Application Data [63] Continuation-in-part of Ser. No. 845,060, July 25, 1969, abandoned.

Gardner et al., Journal of Org. Chem, XIX, pp. 75 3- 757 (1954).

Primary Examiner-Stanley J. Friedman Attorney-Gordon W. Hueschen and Talivaldis Cepuritis [5 7] ABSTRACT Pharmaceutical compositions containing 2-pyridyl thioacetamide and its salts and method of treating gastroduodenal ulcer and gastric hypersecretion by the same.

15 Claims, No Drawings COMPOSITIONS AND METHOD FOR TREATING GASTRODUODENAL ULCER AND GASTRIC HYPERSECRETION WITH A Z-PYRIDYL TIIIOACETAMIDE OR A SALT THEREOF This application is a continuation-impart of our copending application Ser. No. 845,060 filed on July decrease of the acidity and of the peptic activity and a significant increase of the viscosity of the gastric secretion.

B. Method of Gl-IOSH and SCHILD Brit. J. Pharmacol. l3 54(1958) The acidity of the gastric secretion is measured in 25, 1969, now abandoned.

The present invention relates to new pharmaceutical compositions containing 2-pyridy1 thioacetamide of rats after stimulation by intravenous injection of 2p.g/kg of pentagastrine.

The results are reported in table 2.

formula 10 DOSES Acid Output yEq/IO minutes Inhibition I 8 mg/kg [.V. before after CHz- C treatment treatment N H: 5,4 I5 75 6,2 1,3 79 This compound was synthetlzed by Gardner T. S. & 5 mg/kg 9,8 3,8 612 a]. [J of Org. Chem. XIX. 753-757, 1954)]. Tested in W .6 the chemotherapy of tuberculosis, it was found devoid Average g' g'g 381 of any activity. 20 2,5 mg/kg 515 is 5217 t w now su risi l f und t at 2- 'd 1 IV 43 214 1 I as rp y h Pym y Average 4,53i0,87 2,43i0,l 45,415,7 1

thioacetamide possesses an outstanding antisecretory and antiulcer activity on the stomach. This activity was evidenced by the following pharmacological tests:

1. Ulcer of restraint [S. Bonfils et al. Rev. Fr. Et. Clin. Biol. X1 343 (1966)]. When administered orally at the dose of mg/kg, the product protects 50 percent, and at the dose of 100 mgjkg, 75 percent of rats against ulceration.

4. Administered to mice at doses of 20, 50, 100 and 200 mg/kg orally, the product has no activity on the gastrointestinal motricity.

5. The product has no activity on the autonomous nervous system, either on isolated organs in vitro,

2. Histamine-Ulcer [Kowalewsky Arch. Intemat. nor on acetylcholine, adrenaline or histamine ac- Pharmacodyn. 170 66 (1967)]. The product tivity in vivo. decreases by percent the ulcer-index in guinea 6. Doses of 100 mg/kg P.O. of the product do not pigs submitted to experimental histamine ulceraexert any activity on the central nervous system of tion. rat and mice. 3.Activity on the gastric secretion. 35 7. The toxicity of 2-pyridyl thioacetamide is very A. Method of H. SHAY et al. Gastroenterology. weak. The LD in mice is 570 mg/kg P.O. and 314 5, 43 (1945). The results are reported in table 1. n ng/lrg [.P.

TABLE 1 Free 1101 Total 11 Cl Nu. K

lupslnv Vlscosl)osus,mg./kg. Volume p11 Cone. Output Cone. Output Cone. Output (Jone. Output i y 1.1). 1 1 1 1 1 1 1 1 T 1 Activity Output 1 X XX XX X X 1 35.5 11.7 28.3 55.5 17.8 48.9 45.7 12.0 81.5 119.5 15.5 30 8.6

xx xx xxx xx xx xx xxx XX 2 51.5 35.5 42.9 57.7 29.5 51.4 59 23.5 133 721.5 112.5 401 15.4

XXX XX XXX XXX XX XXX XXX X XXX XX XXX XXX 5 71 153 79.8 94.5 51.5 95.5 102.9 37.9 200.5 12.3 24.4 51.7 21.5

XXX XXX XXX XXX XXX XXX XXX 20 50.7 307.5 100 100 95.5

131. 6 Insufiicient quantities In this table, the figures represent the decrease l This weak toxicity and the here-above described proor increase t in percent, in comparison with the parties of 2-pyridyl thioacetamide permit its use in controls after intraduodenal administration of the therapy, especially in the treatment of gastric hyperproduct. secretion and gastroduodenal ulcer.

2-pyridyl thioacetamide is a substance of basic character and can so easily converted in addition salts with mineral and organic acids, such, for example, as hydrochloric, hydrobromic, sulfric, phosphoric, tartaric, citric, acetic, lactic, salicylic, methane sulfonic, fu-

l Pepsine is understood as the whole proteolytic activity at pH 1,8 2 of the gastric secretion, determined by the autoanalyzer. 2. Viscosity was determined by the viscosimeter of Broukfield at constant temperature.

The figures of this table clearly show an important maric, maleic and similar pharmaceutically lactic, salicylic, methane sulfonic, fumaric, acids.

It can be administered in various pharmaceutical forms, such, for example, as tablets, dragees, capsules, suppositories or solutions in admixture or conjunction with different pharmaceutical solid or liquid carriers The doses may vary from 50 to 500mg, preferably 150 to 300 mg, two to three times per day in oral, rectal or parenteral administration.

The following examples illustrate the process for preparing 2-pyridyl thioacetamide and its salts.

EXAMPLE 1 23,6 g (0,2 mol.) of pyridyl acetronitrile, dissolved in 25 ml of triethylamine and 20 g of anhydrous pyridine is saturated with hydrogen sulphide. The reaction mixture is evaporated to dryness. The oily residue is recrystallized in 170 ml of water.

23 g of product are obtained, M.P. 8889 C (Kofler). 19 g of this product are dissolved in 250 ml of dry ethanol. There is added under stirring a slight excess of dry hydrochloric acid in ether solution. The hydrochloride is recrystallized from aqueous ethanol. Yield 18 g M.P. 190-l 92 C (Kofler inst.).

The following salts were prepared in the same way as inEx ample 1:

EXAMPLE 2 2-pyridyl thioacetamide citrate, M.P. l46-l47 C (decomp) EXAMPLE 3 2-pyridyl thioacetamide sulfate, M.P. ll8120 C (decomp) EXAMPLE 4 2-pyridyl thioacetamide phosphate, M.P. l50-152 EXAMPLE 5 2-pyridyl thioacetamide fumarate, M.P. l42-l 44 C EXAMPLE 6 2-pyridyl thioacetamide maleate, MP. l30-132 C (decomp) EXAMPLE 7 Z-pyridyl thioacetamide d. tartarate, M.P. l4l-l42 C The following examples illustrate the pharmaceutical compositions containing Z-pyridyl thioacetamide.

TABLETS EXAMPLE 8 Z-pyridyl thioacetamide, hydrochloride 0,100 g Starch 0,125 g Glucose 0,010 g Talc 0,020 g Magnesium Stearate 0,005 g L B 1 .3 .lEL Q'IIQN Z-pyridyl thioacetamide, HC] 250 mg Distilled water q.s. to ID ml What we claim is:

l. A pharmaceutical composition in dosage unit form adapted to treat gastroduodenal ulcer or gastric hypersecretion, containing as an active ingredient an effective antisecretory amount of about 50 to about 500 milll of 2- 'd 1 th' 'd h t'- c lg ccepteilil e cid c idi ti ii s lt t h r o to g e t e r 4. The pharmaceutical composition as claimed in claim 1, containing as active ingredient 2-pyridyl thioacetamide phosphate.

5. The pharmaceutical composition as claimed in claim 1, containing as active ingredient Z-pyridyl thioacetamide fumarate.

6. The pharmaceutical composition as claimed in claim 1, containing as active ingredient Z-pyridyl thioacetamide maleate.

7. The pharmaceutical composition as claimed in claim 1, containing as active ingredient 2-pyridyl thioacetamide d. tartarate.

8. The pharmaceutical composition as claimed in claim 1, containing as active ingredient 2-pyridyl thioacetamide hydrochloride.

9. The pharmaceutical composition as claimed in claim 1, wherein the active ingredient is present in an amount of 150 to 300 milligrams.

10. The pharmaceutical composition of claim 1, in an injectable form containing 250 milligrams of the active ingredient.

11. The pharmaceutical composition of claim 1 in tablet form containing milligrams of the active ingredient.

12. A method of treating a living animal body suffering from gastric ulcer or hypersecretion, which consists of administering to said living animal body an effective antisecretory amount of 2-pyridyl thioacetamide or a pharmaceutically suitable acid addition salt thereof.

13. The method as claimed in claim 12 wherein the antisecretory compound is administered in unit dosage form containing 50 to 500 milligrams of the active antisecretory ingredient.

14. The method as claimed in claim 12 wherein the antisecretory compound is administered orally.

15. The method as claimed in claim 12 wherein the antisecretory compound is administered parenterally. 

2. The pharmaceutical composition as claimed in claim 1, containing as active ingredient 2-pyridyl thioacetamide citrate.
 3. The pharmaceutical composition as claimed in claim 1, containing as active ingredient 2-pyridyl thioacetamide sulfate.
 4. The pharmaceutical composition as claimed in claim 1, containing as active ingredient 2-pyridyl thioacetamide phosphate.
 5. The pharmaceutical composition as claimed in claim 1, containing as active ingredient 2-pyridyl thioacetamide fumarate.
 6. The pharmaceutical composition as claimed in claim 1, containing as active ingredient 2-pyridyl thioacetamide maleate.
 7. The pharmaceutical composition as claimed in claim 1, containing as active ingredient 2-pyridyl thioacetamide d. tartarate.
 8. The pharmaceutical composition as claimed in claim 1, containing as active ingredient 2-pyridyl thioacetamide hydrochloride.
 9. The pharmaceutical composition as claimed in claim 1, wherein the active ingredient is present in an amount of 150 to 300 milligrams.
 10. The pharmaceutical composition of claim 1, in an injectable form containing 250 milligrams of the active ingredient.
 11. The pharmaceutical composition of claim 1 in tablet form containing 100 milligrams of the active ingredient.
 12. A method of treating a living animal body suffering from gastric ulcer or hypersecretion, which consists of administering to said living animal body an effective antisecretory amount of 2-pyridyl thioacetamide or a pharmaceutically suitable acid addition salt thereof.
 13. The method as claimed in claim 12 wherein the antisecretory compound is administered in unit dosage form containing 50 to 500 milligrams of the active antisecretory ingredient.
 14. The method as claimed in claim 12 wherein the antisecretory compound is administered orally.
 15. The method as claimed in claim 12 wherein the antisecretory compound is administered parenterally. 